Process for preparing 1,4-dihydro-2-amino-3-carboxy-5-cyano-pyridine derivatives

ABSTRACT

The present invention relates to new 2-amino-5-cyano-4-quinoline-1,4-dihydropyridines, processes for their preparation and their use in medicaments, in particular in agents for the treatment of cardiovascular diseases.

This application is a divisional of application Ser. No. 08/006,432,filed Jan. 21, 1993, U.S. Pat. No. 5,380,851, which is a division ofapplication Ser. No. 07/886,644, filed May 20, 1992, now U.S. Pat. No.5,225,558.

The present invention relates to new2-amino-5-cyano-4-quinoline-1,4-dihydropyridines, processes for theirpreparation and their use in medicaments, in particular in agents forthe treatment of cardiovascular diseases.

It is already known that some 2- and 6-amino-3,4-dihydropyridines alsohave a lipid absorption-inhibiting action, in addition to anantiarrhythmic action [compare EP 73,997].

2-Amino-1,4-dihydropyridines have furthermore been described, in somecases also with a vasodilatory and antihypertensive action [compare, forexample, DE 2,242,786].

Knowing these properties of dihydropyridines, it was not foreseeablethat the compounds according to the invention would have a contractionforce-intensifying action which is positively inotropic on the cardiacmuscle, coupled with a largely vasoneutral behaviour.

Some of the compounds of the formula (I) according to the invention fallunder the general claim in EP 71,819, but without a concrete substancerepresentative being mentioned therein.

The present invention relates to2-amino-5-cyano-4-quinoline-1,4-dihydropyridines of the general formula(I) ##STR1## in which R¹ represents aryl having 6 to 10 carbon atoms,which is optionally substituted up to 3 times, in an identical ordifferent manner, by halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy or trifluoromethylthio, or by straight-chain orbranched alkyl having up to 8 carbon atoms, which can in turn besubstituted by aryl having 6 to 10 carbon atoms, or is substituted bystraight-chain or branched alkoxy or alkoxycarbonyl having in each caseup to 8 carbon atoms, carboxyl or amino, or by a group of the formula--NR⁴ R⁵, wherein R⁴ and R⁵ are identical or different and denotestraight-chain or branched alkyl having up to 8 carbon atoms, phenyl orbenzyl, or represents thienyl,

R² represents hydrogen, or represents cycloalkyl having 5 to 8 carbonatoms, or represents straight-chain or branched alkyl, alkenyl,alkadienyl or alkinyl having in each case up to 10 carbon atoms, whichare optionally substituted once or twice, in an identical or differentmanner, by halogen, hydroxyl, carboxyl, cyano or nitro, or bystraight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl oracyloxy having in each case up to 8 carbon atoms, or by cycloalkylhaving 3 to 8 carbon atoms, phenoxy or phenyl, it being possible for thelatter in turn to be substituted up to twice, in an identical ordifferent manner, by halogen or by straight-chain or branched alkyl oralkoxy having in each case up to 6 carbon atoms, or are substituted bythe group --NR⁴ R⁵, wherein R⁴ and R⁵ have the abovementioned meaning,and

R³ represents hydrogen or straight-chain or branched alkyl having up to8 carbon atoms,

and physiologically acceptable salts thereof.

Physiologically acceptable salts are salts of the compounds according tothe invention with inorganic or organic acids. Salts with inorganicacids, such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid or sulphuric acid, or salts with organic carboxylic orsulphonic acids, such as, for example, acetic acid, maleic acid, fumaricacid, malic acid, citric acid, tartaric acid, lactic acid or benzoicacid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonicacid, toluenesulphonic acid or naphthalenedisulphonic acid, arepreferred.

The compounds according to the invention exist in stereoisomeric formswhich are either mirror images (enantiomers) or not mirror images(diastereomers). The invention relates both to the antipodes and to theracemic forms, as well as to the diastereomer mixtures. The racemicforms, like the diastereomers, can be separated into thestereoisomerically uniform constituents in a known manner (compare E. L.Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Preferred compounds are those of the general formula (I) in which

R¹ represents phenyl, which is optionally substituted up to 3 times, inan identical or different manner, by halogen, nitro, cyano ortrifluoromethyl, or by straight-chain or branched alkyl or alkoxy havingin each case up to 6 carbon atoms, benzyl or by a group of the formula--NR⁴ R⁵, wherein R⁴ and R⁵ are identical or different and denotehydrogen, straight-chain or branched alkyl having up to 6 carbon atoms,phenyl or benzyl, or represents thienyl, represents hydrogen,

R² or represents cyclopentyl or cyclohexyl, or represents straight-chainor branched alkyl or alkenyl having in each case up to 10 carbon atoms,which are optionally substituted by halogen, hydroxyl, carboxyl orcyano, or by straight-chain or branched alkylthio, alkoxycarbonyl,alkoxy, acyl or acyloxy having in each case up to 6 carbon atoms,cyclopropyl, cyclopentyl, cyclohexyl, phenoxy or phenyl, it beingpossible for the last two to be substituted by halogen, methyl, methoxyor ethoxy, or are substituted by the group --NR⁴ R⁵, wherein R⁴ and R⁵have the abovementioned meaning, and

R³ represents hydrogen or straight-chain or branched alkyl having up to6 carbon atoms, and physiologically acceptable salts thereof.

Particularly preferred compounds are those of the general formula (I) inwhich

R¹ represents phenyl, which is optionally substituted up to twice, in anidentical or different manner, by fluorine, chlorine, nitro ortrifluoromethyl, or by straight-chain or branched alkyl or alkoxy havingin each case up to 4 carbon atoms, or by a group of the formula --NR⁴R⁵, wherein R⁴ and R⁵ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms, phenyl orbenzyl, or represents thienyl, represents hydrogen, or

R² represents cyclopentyl, or represents straight-chain or branchedalkyl having up to 8 carbon atoms, which is optionally substituted byfluorine, chlorine, hydroxyl, carboxyl or cyano, or by straight-chain orbranched alkoxycarbonyl, alkoxy or acyloxy having in each case up to 4carbon atoms, phenyl, phenoxy, cyclopropyl, cyclopentyl or cyclohexyl,or by the group --NR⁴ R⁵, wherein R⁴ and R⁵ have the abovementionedmeaning, and

R³ represents hydrogen, or represents straight-chain or branched alkylhaving up to 4 carbon atoms,

and physiologically acceptable salts thereof.

The preparation of the compounds of the general formula (I) according tothe invention is characterized in that [A] either aldehydes of thegeneral formula (II) ##STR2## in which R¹ has the abovementionedmeaning, are reacted directly with compounds of the general formula(III) ##STR3## in which R³ has the abovementioned meaning, and compoundsof the tautomeric formulae (IV) or (IVa) ##STR4## in which R² has theabovementioned meaning, in inert solvents at temperatures between 10° C.and 150° C., [B] or ylidene compounds of the general formula (V)##STR5## in which R¹ and R³ have the abovementioned meaning, are reactedwith compounds of the general formula (VI) or (VIa) ##STR6## in which R²has the abovementioned meaning and X represents the amino group or thegroup OR⁶, wherein R⁶ represents C₁ -C₄ -alkyl, if appropriate in thepresence of inert organic solvents at temperatures of 10° C. to 150° C.,ammonium salts, such as ammonium acetate being added in the case where Xrepresents the group OR⁶.

In the case of the pure enantiomers, either the diastereomer mixtureformed from the particular compounds of the general formula (I) in whichR² represents a defined chiral radical is first separated and thenconverted into the corresponding carboxylic acids (R² ═H), which areesterified in a final step, or the particular diastereomers aretransesterified directly with the corresponding alcohols, in particularin the form of the alcoholates.

The processes according to the invention can be illustrated by way ofexample by the following equation: ##STR7##

Suitable solvents here are all the inert organic solvents which do notchange under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, acetonitrile, or amides, such ashexamethylphosphoric acid triamide or dimethylformamide, or acetic acid,alkyl acetates or halogenated hydrocarbons, such as methylene chlorideor carbon tetrachloride, or hydrocarbons, such as benzene or toluene. Itis also possible to use mixtures of the solvents mentioned. Methanol,isopropanol, ethanol and n-propanol, acetonitrile or tetrahydrofuran arepreferred, depending on the particular process variant [A] or [B].

The reaction temperatures can be varied within a relatively wide range.The reaction is in general carried out between +10° C. and +150° C.,preferably between +20° C. and 100° C., in particular at the boilingpoint of the particular solvent.

The reaction can be carried out under normal pressure, but also underincreased or reduced pressure (for example 0.5 to 3 bar). It is ingeneral carried out under normal pressure.

Suitable chiral ester radicals are all the esters of enantiomericallypure alcohols, such as, for example, 2-butanol, 1-phenylethanol, lacticacid, lactic acid esters, mandelic acid, mandelic acid esters,2-aminoalcohols, sugar derivatives, hydroxyamino acid derivatives andmany other enantiomerically pure alcohols.

The diastereomers are in general separated either by fractionalcrystallisation, by column chromatography or by Craig partition. Whichprocess is the optimum must be decided from case to case, and it issometimes also advantageous to use combinations of the individualprocesses. Separation by crystallisation or Craig partition or acombination of the two processes is particularly suitable.

The compounds of the general formula (II) are known in some cases andcan be prepared by customary methods, for example by oxidising thecorresponding alkyl- or hydroxy-alkyl-quinolines or reducing thecorresponding carboxyquinolines (compare also German Offenlegungsschrift4,011,105).

Alternatively, 4-amino-3-hydroxyphthalide, which is obtained bycustomary hydrogenation of 4-nitro-3-hydroxyphthalide which is knownfrom the literature [T. Watanabe et al., Chem. Pharm. Bull. 20 (10),2123-2127 (1970)] in the presence of a catalyst, preferably withpalladium/barium sulphate, can also be reacted with compounds of thegeneral formula R¹ --CH₂ --CHO, some of which are known [compare, forexample, Beilstein 7, 292], to give compounds of the general formula(II) via the corresponding carboxylic acids.

The compounds of the general formula (III ), (IV) and (IVa) are knownper se or can be prepared by methods known from the literature [compareJ. Heterocycl. Chem. 26, 1575 (1989 ); and Liebigs Ann. Chem. 1977,1895-1908].

The ylidene compounds of the general formula (V) are new and can beprepared by a process in which compounds of the general formula (VII)##STR8## in which R³ has the abovementioned meaning, are converted withalkali metal hydroxides or alkali metal alcoholates into the alkalimetal salts of the compounds of the general formula (VIII)

    R.sup.3 --CO--CH.sub.2 --CN                                (VIII)

in which R³ has the above mentioned meaning, and these are reacted,either in situ or after isolation, with aldehydes of the general formula(II) in one of the abovementioned inert solvents, preferably inalcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform orethers, with the addition of acid, preferably acetic acid, and ifappropriate in the presence of a catalyst, for example piperidineacetate, at temperatures between 0° C. and 150° C., preferably between20° C. and 110° C.

The compounds of the general formula (VII) are also known in most cases,or can be prepared by a customary method [compare Helv. Chim. Acta,Volume XLVU, Fasciculens II (1963), No. 56-57, pages 543-556.

The compounds of the general formula (VIII) are also known or can beprepared by methods known from the literature.

The compounds according to the invention exhibit an unforeseeable,useful pharmacological action spectrum. They influence the contractionforce of the heart and the tone of the smooth muscle. Preferably, theyexhibit a positively inotropic action. They can therefore be employed inmedicaments for influencing pathologically changed blood pressure, ascoronary therapeutics and for the treatment of cardiac insufficiency.They can moreover be used for the treatment of disturbances in cardiacrhythm, for reducing blood sugar, for detumescing mucosa and forinfluencing the salt and fluid balance.

The cardiovascular actions were found on the isolated perfused heart ofthe guineapig. The hearts of guineapigs weighing 250 to 350 g are usedfor this. The animals are sacrificed with a blow on the head, the thoraxis opened and a metal cannula is inserted into the exposed aorta. Theheart is removed from the thorax with the lung and connected via anaorta cannula to the perfusion apparatus with the perfusion running. Thelungs are removed at the lung roots, and the perfusion medium used is aKrebsHenseleit solution (1) (118.5 mmol/l of NaCl, 4.75 mmol/l of KCl,1.19 mmol/l of KH₂ PO₄, 1.19 mmol/l of MgSO₄, 25 mmol/l of NaHCO₃ and0.013 mmol/l of Na₂ EDTA), the CaCl₂ content of which is 1.2 mmol/l. 10mmol/l of glucose are added as the energy-supplying substrate. Beforethe perfusion, the solution is filtered free from particles. Thesolution is gassed with carbogen (95% of O₂, 5% of CO₂) to maintain thepH of 7.4. The hearts are perfused at a constant flow rate (10ml/minute) at 32° C. by means of a roller squeeze pump.

To measure the cardiac function, a latex balloon filled with liquid andconnected to a pressure transducer via a column of liquid is insertedthrough the left atrium into the left ventricle, and the isovolumetriccontractions are recorded on a high-speed recorder (Opie, L., J.Physiol. 180 (1965), 529-541). The perfusion pressure is recorded bymeans of a pressure transducer connected to the perfusion systemupstream of the heart. Under these conditions, a reduction in theperfusion pressure indicates coronary dilation and an increase ordecrease in the left ventricular contraction amplitude indicates areduction or an increase in cardiac contractility. The compoundsaccording to the invention are perfused into the perfusion system insuitable dilutions shortly upstream of the isolated heart.

Substance effects on the contraction amplitude of isolated-guineapigatria at an active compound concentration of 10.4 g/l.

    ______________________________________                                        Example No. Contraction force (% of control)                                  ______________________________________                                         6          +14                                                                7          +103                                                              13          +21                                                               14          +43                                                               ______________________________________                                    

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should in each case be present here in aconcentration of about 0.5 to 90% by weight of the total mixture, thatis to say in amounts which are sufficient to achieve the stated dosagerange.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifying agents and/or dispersing agents, it being possible, forexample in the case where water is used as a diluent, for organicsolvents to be used as auxiliary solvents if appropriate.

Administration takes place in the customary manner, preferably orally orparenterally, in particular perlingually or intravenously.

In general it has proved advantageous in the case of intravenousadministration to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg of body weight, to achieve effectiveresults, and in the case of oral administration the dosage is about 0.01to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may be necessary, if appropriate, to deviate from theamounts mentioned, and in particular to do so as a function of the bodyweight or type of administration route, the behaviour of the individualtowards the medicament, the nature of the formulation thereof and thetime or interval at which administration takes place. Thus in some casesit may be sufficient to manage with less than the abovementioned minimumamount, while in other cases the upper limit mentioned must be exceeded.Where relatively large amounts are administered, it may be advisable todistribute these into several individual doses over the day.

STARTING COMPOUND Example I

1- (3-Phenylquinol-5-ylidene ) -3-oxo-butyronitrile ##STR9##

15.45 g (66.3 mmol) of 3-phenyl-quinoline-5-aldehyde are boiled in 420ml of methylene chloride with 6.97 g (66.4 mmol) of 3-oxo-butyronitrilesodium salt (obtained by dissolving 5-methylisoxazole in the equivalentamount of sodium methylate solution and concentrating the solution),4.34 ml of acetic and 0.66 ml of piperidine for 24 hours, using a waterseparator. The mixture is cooled, washed twice with water, filtered toremove a little by-product which has precipitated, and concentrated. Thedesired product crystallises on stirring with ethanol. 12.7 g of yellowcrystals of melting point 142° C. to 144° C. are obtained.

Example 1 (process B)

(S)-(1-Methoxycarbonyl)-ethyl-2-amino-1,4-dihydropyridine-5-cyano-6-methyl-4-(3-phenylquinolin-5-yl)-3carboxylate##STR10##

Method A

2,5 g (8.4 mmol) of 1-(3-phenylquinol-5-ylidene)-3-oxobutyronitrile areboiled overnight in 15 ml of isopropanol with 2.2 g (10.1 mmol) of(S)-(1-methoxycarbonyl)-ethyl 3-immino-3-ethoxy-acetate and 1.43 g(18.44 mmol) of ammonium acetate. The mixture is concentrated, theresidue is taken up in ethyl acetate and the mixture is washed twicewith water, dried and concentrated. The resulting diastereomer mixtureis separated over a silica gel column using methylene chloride/ethylacetate mixtures of 10:1 to 2:1, and the pure fractions are collectedand concentrated. 1.25 g of the diastereomer A (R_(f) value=0.27;TLC-aluroll, Merck, silica gel 60, F 254) and 778 mg of the crystallinedeastereomer B of melting point: 274°-276° C. and R_(f) value 0.20 areobtained

Method B

2.5 g (8.4 mmol) of 1-(3-phenylquinol-5-ylidene)-3-oxo-butyronitrile areboiled for three hours in 10 ml ethylacetate with 2.2 g (10.1 mmol) of(S)-1-methoxycarbonyl)-ethyl 3-imino-3-ethoxy-acetate and 1.43 g (18.44mmol) of ammonium acetate. After cooling the precipitated crystals werefiltered off with

PREPARATION EXAMPLES Example 1

Ethyl(-)-2-amino-1,4-dihydropyridine-5-cyano-6-methyl-4-(3-phenylquinolin-5-yl)-3-carboxylate##STR11##

1.3 g (2.76 mmol) of the diastereomer B from Example 1 are added to asolution of 200 mg (28.3 mmol) of lithium in 25 ml of ethanol. Themixture is heated at the boiling point for 30 minutes, cooled andconcentrated. The evaporation residue is taken up in ethylacetate/water, the phases are separated and the organic phase is washedtwice with water and concentrated. The resulting product is purified byflash chromatography and crystallised with acetonitrile. 678 mg ofcolourless crystals of melting point 195°-198° C. are obtained.

Example 3 (process A)

Isopropyl2-amino-1,4-dihydro-5-cyano-6-methyl-4-(3-phenyl-quinolin-5-yl)-pyridine-3-carboxylate##STR12##

4.66 g (20 mmol) of 3-phenyl-quinoline-5-aldehyde are boiled in 40 ml ofisopropanol with 1.64 g (20 mmol) of 3-aminocrotononitrile, 3.6 g (20mmol) of isopropyl amidinoacetate hydrochloride and 1.64 g (20 mmol) ofsodium acetate for 20 hours. The mixture is concentrated, the residue istaken up in ethyl acetate/water and the phases are separated. Theorganic phase is washed twice with water, dried and concentrated. Thereaction mixture is separated over a silica gel column using methylenechloride/ethyl acetate mixtures. The desired fractions are collected andconcentrated. The resulting evaporation residue is crystallised withacetonitrile and filtered off with suction. 635 mg of colourlesscrystals of melting point 227°-229° C. are obtained.

Example 4

Isopropyl2-amino-1,4-dihydropyridine-5-cyano-6-methyl-4-(3-(3-chlorophenyl)-quinolin-5-yl)-carboxylate##STR13##

1.66 g (5 mmol) of1-[3-(3-chlorophenyl)-quinol-5-ylidene]-3-oxo-butyro-nitrile are heatedunder reflux overnight in 10 ml of isopropanol with 905 mg (5 mmol) ofisopropyl amidinoacetate hydrochloride and 410 mg (5 mmol) of sodiumacetate. The mixture is cooled and concentrated. The resultingevaporation residue is dissolved in ethyl acetate/water, the phases areseparated and the organic phase is washed with sodium bicarbonatesolution and twice with water, dried and concentrated. Colourlesscrystals of melting point 264°-265° C. are obtained by stirring withacetonitrile.

Example 5 (Process B without isolation of the intermediate product)

n-Propyl2-amino-1,4-dihydro-5-cyano-6-methyl-4-(3-phenylquinolin-5-yl)-pyridine-3-carboxylate##STR14##

23.3 g (100 mmol) of 3-phenyl-quinoline-5-aldehyde are suspended in 200ml of n-propanol and the suspension is stirred with 8.25 ml (100 mmol)of 5-methylisoxazole. A solution of 2.3 g of sodium in 100 ml ofn-propanol is added dropwise and the mixture is stirred at 40°-50° C.for 4 hours. A brown solution is obtained by this procedure. 18.04 g(100 mmol) of propyl amidinoacetate hydrochloride and 6 ml of aceticacid (100 mmol) are added and the mixture is boiled for 20 hours. It isconcentrated, the residue is dissolved in ethyl acetate/water and thephases are separated. The ethyl acetate phase is washed with sodiumbicarbonate solution and twice with water, dried and concentrated. Theresulting residue is dissolved in 100 ml of hot acetonitrile and theproduct is left to crystallise. It is filtered off with suction andrecrystallised from n-propanol and then from acetonitrile. 6.9 g ofcolourless crystals of melting point 237° C. are obtained.

The examples listed in Table 1 are prepared analogously to theinstructions of Examples 1-5:

                  TABLE 1                                                         ______________________________________                                         ##STR15##                                                                    Ex-                                                                           ample                           Melting                                                                              Enan-                                  No.   R.sup.1  R.sup.2          point °C.                                                                     tiomer                                 ______________________________________                                         6    H        C.sub.2 H.sub.5  174-77                                         7    H        CH.sub.3         230                                            8    4-F      C.sub.2 H.sub.5  186-88                                         9    4-F                                                                     n-C.sub.3 H.sub.7                                                                   226-28                                                                  10    4-F      CH.sub.3         214-16                                        11    4-F      CH(CH.sub.3).sub.2                                                                             226-28                                        12    H        CH.sub.2CH.sub.2OCH.sub.3                                                                      248                                           13    H        n-C.sub.3 H.sub.7                                                                              191-92 (-)                                    14    H        CH(CH.sub.3).sub.2                                                                             263-65 (-)                                    15    H                                                                                       ##STR16##       262    (-)                                    16    3-F      n-C.sub.3 H.sub.7                                                                              219                                           17    3-F      C.sub.2 H.sub.5  248                                           18    H        CH(CH.sub.3)CH.sub.2CH.sub.3                                                                   Foam   (-)                                    19    H        CH.sub.3         262    (-)                                    20    H                                                                       n-C.sub.4 H.sub.9                                                                   188      (-)                                                            21    H        n-C.sub.5 H.sub.11                                                                             120    (-)                                    22    H                                                                                       ##STR17##       211-12                                        23    4-OCH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                             264                                           24    3-F      CH(CH.sub.3).sub.2                                                                             204-06                                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR18##                                                                    Example No.   R.sup.2  Melting point °C.                               ______________________________________                                        25                                                                            n-C.sub.3 H.sub.7      173-76                                                 26            CH.sub.3 186-89                                                 ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR19##                                                                    Ex-                                                                           ample                           Melting                                                                              Enan-                                  No.   R.sup.1   R.sup.2         point °C.                                                                     tiomer                                 ______________________________________                                        27    H         CH(CH.sub.3).sub.2                                                                            204                                                                           (hydro-                                                                       chloride)                                     28    2-F       CH(CH.sub.3).sub.2                                                                            234                                           29    2-F       CH.sub.2CH.sub.2CH.sub.3                                                                      204-5                                         30    4-F                                                                     nC.sub.3 H.sub.7                                                                    217-19    (-)                                                           31    4-F       CH(CH.sub.3).sub.2                                                                            270-71 (-)                                    32    H         (CH.sub.2).sub.2OC.sub.2 H.sub.5                                                              189    (-)                                    33    H         CH.sub.2CH(CH.sub.3).sub.2                                                                    197    (-)                                    34    H         CH.sub.2CH.sub.2C.sub.6 H.sub.5                                                               145    (-)                                    35    H         CH.sub.2C.sub.6 H.sub.5                                                                       225    (-)                                    36    H                                                                                        ##STR20##      225    (-)                                    37    H         (CH.sub.2).sub.2OC.sub.6 H.sub.5                                                              150    (-)                                                                    (decom-                                                                       position)                                     38    H         (CH.sub.2).sub.2OCH.sub.3                                                                     155    (-)                                    39    H         (CH.sub.2).sub.2OH                                                                            179    (-)                                    40    3-NO.sub.2                                                                              (CH.sub.2).sub.2CH.sub.3                                                                      183                                           41    3-NO.sub.2                                                                              CH(CH.sub.3).sub.2                                                                            248                                           42    H                                                                                        ##STR21##      Foam   (-)                                    43    H                                                                                        ##STR22##      260    (-)                                    44    2-CF.sub.3                                                                              CH(CH.sub.3).sub.2                                                                            212                                           45    2-CF.sub.3                                                                              n-C.sub.3 H.sub.7                                                                             182                                           46    3,4-OCH.sub.3                                                                           CH(CH.sub.3).sub.2                                                                            264                                           ______________________________________                                    

We claim:
 1. Process for the preparation of compounds of the generalformula (I) ##STR23## in which R¹ represents aryl having 6 to 10 carbonatoms, which is optionally substituted up to 3 times, in an identical ordifferent manner, by halo gen, nitro, cyano, trifluoromethyl, trifluoromethoxy or trifluoromethylthio, or by straight-chain or branched alkylhaving up to 8 carbon atoms, which can in turn be substituted by arylhaving 6 to 10 carbon atoms, or is substituted by straight-chain orbranched alkoxy or alkoxycarbonyl having in each case up to 8 carbonatoms, carboxyl or amino, or by a group of the formula --NR⁴ R⁵, whereinR⁴ and R⁵ are identical or different and denote straight-chain orbranched alkyl having up to 8 carbon atoms, phenyl or benzyl, orrepresents thienyl,R² represents hydrogen, or represents cycloalkylhaving 5 to 8 carbon atoms, or represents straight-chain or branchedalkyl, alkenyl, alkadienyl or alkinyl having in each case up to 10carbon atoms, which are optionally substituted once or twice, in anidentical or different manner, by halogen, hydroxyl, carboxyl, cyano ornitro, or by straight-chain or branched alkylthio, alkoxy,alkoxycarbonyl, acyl or acyloxy having in each case up to 8 carbonatoms, or cycloalkyl having 3 to 8 carbon atoms, or by phenoxy orphenyl, it being possible for the latter in turn to be substituted up totwice, in an identical or different manner, by halogen or by straightchain or branched alkyl or alkoxy having in each case up to 6 carbonatoms, or are substituted by the group --NMR⁴ R⁵, wherein R⁴ and R⁵ havethe abovementioned meaning, and R³ represents hydrogen or straight-chainor branched alkyl having up to 8 carbon atoms, and physiologicallyacceptable salts thereof, characterized in that either aldehydes of thegeneral formula (II) ##STR24## in which R¹ has the abovementionedmeaning, are reacted directly with compounds of the general formula(III) ##STR25## in which R³ has the abovementioned meaning, andcompounds of the tautomeric formulae (IV) or (IVa) ##STR26## in which R²has the abovementioned meaning, in inert solvents at temperaturesbetween 10° C. and 150° C., or ylidene compounds of the general formula(V) ##STR27## in which R¹ and R³ have the abovementioned meaning, arereacted with compounds of the general formula (VI) or (VIa) ##STR28## inwhich R² has the abovementioned meaning and X represents the amino groupor the group OR⁶, whereinR⁶ represents C₁ -C₄ -alkyl,if appropriate inthe presence of inert organic solvents at temperatures of 10° C. to 150°C., ammonium salts, such as ammonium acetate being added in the casewhere X represents the group OR⁶.